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1.
晚期糖基化终产物激活内皮细胞核因子κB   总被引:1,自引:1,他引:0       下载免费PDF全文
目的 探讨晚期糖基化终产物对人血管内皮细胞核因子κB的激活及作用机制.方法 用晚期糖基化终产物修饰的人血清白蛋白与人脐静脉内皮细胞株ECV304体外共同培养.用Western blot检测核因子κB抑制蛋白水平,凝胶滞留法检测核因子κB的活性.结果 晚期糖基化终产物修饰的人血清白蛋白可致ECV304核因子κB抑制蛋白降解及核因子κB激活,并且呈时间、剂量依赖关系,抑制核因子κB抑制蛋白的降解,可抑制核因子κB的激活.结论 晚期糖基化终产物修饰的人血清白蛋白通过引起核因子κB抑制蛋白降解,导致核因子κB的激活,这一作用机制可能参与动脉粥样硬化的进程.  相似文献   

2.
晚期糖基化终产物诱导血管内皮细胞环氧合酶2表达   总被引:1,自引:1,他引:0       下载免费PDF全文
目的探讨晚期糖基化终产物对人血管内皮细胞环氧合酶2表达的影响。方法取人脐静脉内皮细胞ECV304与人血清白蛋白修饰的晚期糖基化终产物体外共同培养,然后用Western blot检测环氧合酶2的表达水平。结果内皮细胞环氧合酶2基础表达水平极低,人血清白蛋白修饰的晚期糖基化终产物可诱导环氧合酶2的表达,呈时间与剂量依赖关系;抑制核因子κB的活性可抑制环氧合酶2的表达。结论人血清白蛋白修饰的晚期糖基化终产物可通过激活核因子κB,而引起环氧合酶2的表达。这一作用机制可能参与血管损伤反应。  相似文献   

3.
晚期糖基化终产物诱导ECV304细胞株氧化增强的可能机制   总被引:1,自引:0,他引:1  
目的探讨晚期糖基化终产物诱导细胞株ECV304氧化增强的机制。方法取ECV304细胞培养,与不同浓度的晚期糖基化终产物-人血清白蛋白共孵育,或分别经NADPH氧化酶抑制剂Apocynin或蛋白激酶C抑制剂GF109203或酪氨酸蛋白激酶抑制剂Genistein预孵育0.5 h后,再与晚期糖基化终产物—人血清白蛋白共孵育,1h后收集细胞,用细胞色素C法检测O2-.,ThioGlo-1试剂检测还原型谷胱甘肽。结果12.5 mg/L、50 mg/L和200mg/L晚期糖基化终产物—人血清白蛋白可导致ECV304细胞内O2-.从1.37±0.67 nmol/(107.h)增加到3.44±0.40、10.67±0.67和10.93±0.67 nmol/(107.h),使还原型谷胱甘肽从9.54±0.41 nmol/106降低到9.02±0.21、8.41±0.34和8.02±0.18 nmol/106,两者均呈剂量依赖性。Apocynin、GF109203及Genistein均可抑制O2-.的增加及还原型谷胱甘肽的降低。结论晚期糖基化终产物-人血清白蛋白可通过蛋白激酶C和酪氨酸蛋白激酶途径激活NADPH氧化酶,引起ECV304细胞内O2-.产生及还原型谷胱甘肽降低,导致细胞内氧化增强。  相似文献   

4.
目的研究晚期糖基化终产物修饰蛋白对内皮细胞细胞骨架肌动蛋白的形态学影响及特异的糖基化终产物受体和氧化应激在此病理过程中的作用。方法用不同浓度的糖基化终产物修饰人血清白蛋白与人脐静脉内皮细胞株ECV304在体外共同培养不同时间,并设立对照组进行比较,采用免疫荧光染色法显示细胞骨架的形态学改变。结果与对照组相比,糖基化终产物修饰人血清白蛋白以时间和剂量依赖的方式影响内皮细胞骨架肌动蛋白聚合丝状和可溶性单体(或球状)形态的改变。随着糖基化终产物修饰人血清白蛋白作用浓度和时间的增加,丝状肌动蛋白所形成的外周致密带边缘出现锯齿样断裂,趋于变细崩解消散,最终形成由非极性单行排列的肌动蛋白丝组成的应力纤维。可溶性单体表现为向细胞浆和胞膜移位,胞浆区出现点状和丝状染色,细胞间距离明显增大。可溶性糖基化终产物受体的抗体和烟酰胺腺嘌呤二核苷酸磷酸盐氧化酶抑制剂均可阻断糖基化终产物对细胞骨架的影响。结论糖基化终产物修饰蛋白对细胞骨架的影响是通过与内皮细胞上的糖基化终产物受体结合并引起细胞内的氧化应激所介导的,这一作用可能与糖基化终产物所致血管通透性升高有关。  相似文献   

5.
构建携有核因子κB抑制物IκBα的突变体IκBαM的重组腺病毒(AdIκBαM),并感染ECV304血管内皮细胞,采用Westem blot、电泳迁移率变动分析和逆转录-聚合酶链反应等方法研究核因子κB在高浓度葡萄糖刺激的ECV304细胞分泌功能中所起的作用以及阻断其活性对内皮细胞分泌功能的影响。结果发现,高糖能诱导ECV304细胞IκBa的降解和核因子κB的激活,同时上调炎症因子细胞间粘附分子1、单核细胞趋化蛋白1和内皮素1mRNA表达水平,而感染AdlIκBαM的ECV304/IκBαM细胞则能拮抗高糖所致的IκBα降解与核因子κB激活,同时下调这些炎症因子的异常分泌水平。结果提示,核因子κB的激活在高糖所致的内皮细胞分泌功能改变中起中轴作用,抑制核因子κB的活化,有助于改善血管内皮细胞功能。  相似文献   

6.
晚期糖基化终产物诱导内皮细胞黏附连接改变及其机制   总被引:1,自引:0,他引:1  
目的观察不同浓度和时间修饰的糖基化人血清白蛋白作用下,人脐静脉内皮细胞内黏附连接蛋白钙黏着蛋白的形态结构变化,并初步探讨其机制。方法原代培养人脐静脉内皮细胞,分别用不同浓度和时间修饰的糖基化人血清白蛋白处理,用免疫荧光染色法、激光共聚焦显微镜观察钙黏着蛋白在内皮细胞的形态和分布变化。分别用可溶性的修饰的糖基化人血清白蛋白受体的抗体、丝裂原活化蛋白激酶抑制剂或转染重组腺病毒突变体转染预处理后再观察晚期糖基化终产物修饰的人血清白蛋白对内皮细胞形态的影响。结果修饰的糖基化人血清白蛋白以时间和剂量依赖方式引起内皮细胞黏附连接钙黏着蛋白形态结构的改变;丝裂原活化蛋白激酶通路抑制剂(SB203580、PD98059、SP600125)和Rho激酶抑制剂Y27632均可减轻晚期糖基化终产物对钙黏蛋白的影响;转染显性失活的细胞外信号调节激酶上游激酶MEK1和p38丝裂原活化蛋白激酶上游激酶MKK6b及p38显性失活的p38α和p38β重组腺病毒突变体,均可减轻晚期糖基化终产物对钙黏蛋白形态结构的影响,而转染组成性激活的MEK1和MKK6b的重组腺病毒本身即可引起钙黏蛋白形态结构的变化。结论晚期糖基化终产物刺激可以引起钙黏蛋白分布和形态的变化,这一作用可能是丝裂原活化蛋白激酶通路细胞外信号调节激酶、p38丝裂原活化蛋白激酶信号通路和c-jun氨基末端激酶(JNK)/应激激活的蛋白激酶(SAPK)介导的,Rho激酶可能参与此过程。  相似文献   

7.
目的 探讨糖基化终产物在糖尿病动脉粥样硬化形成中的作用机理。方法 分离正常人脐静脉内皮细胞,将糖基化终产物修饰的人血清白蛋白及未修饰人血清白蛋白与人脐静脉内皮细胞在体外共同培养,用荧光单克隆抗体染色,流式细胞仪定量检测内皮细胞表面选择素E的表达。结果 正常人脐静脉内皮细胞未表达选择素Eo糖基化终产物修饰的人血清白蛋白能以时间和剂量依赖的方式上调血管内皮细胞粘附分子选择素E的表达(P〈0.015),而人血清白蛋白对人脐静脉内皮细胞粘附分子选择素E的表达无影响。结论 糖基化终产物能上调人脐静脉内皮细胞粘附分子的表达,从而促进动脉粥样硬化时单核,巨噬细胞的浸润。  相似文献   

8.
核因子kB在脑缺血及再灌注损伤炎症机制中的作用   总被引:3,自引:0,他引:3  
核因子kB是一种重要的转录因子。急性脑缺血再灌注时,核因子活性增高,活化的核因子kB促使黏使分子,即早基因和细胞因子表达,是血管内皮细胞损伤的始动机制之一,在脑缺血再灌注损伤炎症机制中起重要作用,用抗氧化剂,酶阻滞剂或乙酰半胱氨酸可抑制核因子kB的活性及黏附分子表达,缩小脑梗死体积。  相似文献   

9.
目的研究糖基化终末产物(AGEs)对大鼠心脏微血管内皮细胞因子kB(NF-kB)和环氧合酶2(COX-2)表达的影响,探讨AGEs与糖尿病血管病变间的关系。方法体外培养大鼠心脏微血管内皮细胞至亚融和状态时,以不同浓度糖基化白蛋白BSA-AGEs与之作用不同时间后,检测内皮细胞NF-kB及COX-2蛋白的表达。结果25、50、100、200mg/LBSA-AGEs作用后,NF-kB和COX-2蛋白表达呈剂量依赖性增多,100mg/LAGEs作用6、12、24、48h,NF-kB和COX-2蛋白表达呈时间依赖性增多。结论BSA-AGEs可促进体外培养微血管内皮细胞NF-kB和COX-2的表达,其作用可能与NF-kB的活化有关。  相似文献   

10.
为探讨预防动脉粥样硬化的药物普罗布考,维生素C和维生素E是否抑制内皮细胞表面粘附分子表达和白细胞一内皮细胞的粘附,以及这种抑制是否通过影响核因子-kB的活性来实现的,在液体流动小室中进行细胞粘附实验。用ELISA方法测定内皮细胞粘附分子E-选择素的表达;用电泳迁移率分析测定内皮细胞核因子-kB的活性,经肿瘤坏死因子α刺激的内皮细胞核因子-B活性增加,粘附分子E-选择素的表达上调(是基础水平的3.5倍),其表面HL60细胞的粘附增加(是基础水平的4-26倍),而抗氧化剂PDTC使所有这些变化都受到抑制。PDTC浓度为18umol/L时对粘附分子E-选择素的表达呈最大半抑制;PDTC浓度为52umol/L时对内皮细胞表面HL60细胞的粘附呈最大半抑制,普罗布考,维生素C和维生素E对肿瘤坏死因子α诱导的粘附分子表达和HL60细胞与内皮细胞的粘附没有作用,对核因子-kB的活性没有影响,临床上常用的这三种抗氧化剂并未影响作为动脉粥样硬化始动机制之一的E-选择素介导的白细胞-内皮细胞粘附水平。  相似文献   

11.
The immunoneuroendocrine role of melatonin   总被引:19,自引:0,他引:19  
Abstract: A tight, physiological link between the pineal gland and the immune system is emerging from a series of experimental studies. This link might reflect the evolutionary connection between self-recognition and reproduction. Pinealectomy or other experimental methods which inhibit melatonin synthesis and secretion induce a state of immunodepression which is counteracted by melatonin. In general, melatonin seems to have an immunoenhancing effect that is particularly apparent in immunodepressive states. The negative effect of acute stress or immunosuppressive pharmacological treatments on various immune parameters are counteracted by melatonin. It seems important to note that one of the main targets of melatonin is the thymus, i.e., the central organ of the immune system. The clinical use of melatonin as an immunotherapeutic agent seems promising in primary and secondary immunodeficiencies as well as in cancer immunotherapy. The immunoenhancing action of melatonin seems to be mediated by T-helper cell-derived opioid peptides as well as by lymphokines and, perhaps, by pituitary hormones. Melatonin-induced-immuno-opioids (MHO) and lymphokines imply the presence of specific binding sites or melatonin receptors on cells of the immune system. On the other hand, lymphokines such as -γ-interferon and interleukin-2 as well as thymic hormones can modulate the synthesis of melatonin in the pineal gland. The pineal gland might thus be viewed as the crux of a sophisticated immunoneuroendocrine network which functions as an unconscious, diffuse sensory organ.  相似文献   

12.
Relying on a certain degree of abstraction, we can propose that no particular distinction exists between animate or living matter and inanimate matter. While focusing attention on some specifics, the dividing line between the two can be drawn. The most apparent distinction is in the level of structural and functional organization with the dissimilar streams of ‘energy flow’ between the observed entity and the surrounding environment. In essence, living matter is created from inanimate matter which is organized to contain internal intense energy processes and maintain lower intensity energy exchange processes with the environment. Taking internal and external energy processes into account, we contend in this paper that living matter can be referred to as matter of dissipative structure, with this structure assumed to be a common quality of all living creatures and living matter in general. Interruption of internal energy conversion processes and terminating the controlled energy exchange with the environment leads to degeneration of dissipative structure and reduction of the same to inanimate matter, (gas, liquid and/or solid inanimate substances), and ultimately what can be called ‘death.’ This concept of what we call dissipative nature can be extended from living organisms to social groups of animals, to mankind. An analogy based on the organization of matter provides a basis for a functional model of living entities. The models relies on the parallels among the three central structures of any cell (nucleus, cytoplasm and outer membrane) and the human body (central organs, body fluids along with the connective tissues, and external skin integument). This three-part structural organization may be observed almost universally in nature. It can be observed from the atomic structure to the planetary and intergalactic organizations. This similarity is corroborated by the membrane theory applied to living organisms. According to the energy nature of living matter and the proposed functional model, the decreased integrity of a human body's external envelope membrane is a first cause of the structural degradation and aging of the entire organism. The aging process than progresses externally to internally, as in single cell organisms, suggesting that much of the efforts towards the restoration and maintenance of the mechanisms responsible for structural development should be focused accordingly, on the membrane, i.e., the skin. Numerous reports indicate that all parts of the human body, like: bones, blood with blood vessels, muscles, skin, and so on, have some ability for restoration. Therefore, actual revival of not only aging tissue of the human body's membrane, but the entire human body enclosed within, with all internal organs, might be expected. We assess several aging theories within the context of our model and provide suggestions on how to activate the body's own anti-aging mechanisms and increase longevity. This paper presents some analogies and some distinctions that exist between the living dissipative structure matter and inanimate matter, discusses the aging process and proposes certain aging reversal solutions.  相似文献   

13.
Abstract: The effect of swimming at night on rat pineal melatonin synthesis was compared with that of light exposure at night. Rats were forced to swim at 0030 hr (lights out at 2000 hr) and sacrificed by decapitation 15 and 30 min later, immediately after swimming. Other groups of animals were exposed to white light (650μW/cm2) for 15 and 30 min at same time. Swimming caused a rapid and highly significant drop in the melatonin content in the pineal gland; however, the activity of N-acetyltransferase (NAT), the supposed rate limiting enzyme in the melatonin production, was not changed. Despite the drop in pineal melatonin levels, serum concentrations of the indole remained elevated in the rats that swam. In contrast, melatonin levels in the pineal and serum of light exposed rats fell precipitously, accompanied by a significant suppression of NAT activity. Since we anticipated that the strenuous exercise associated with swimming may induce release of artrial natriuretic peptide (ANP) from the heart, which in turn could cause the release of pineal melatonin, in a second study we injected physiological saline intravenously to stretch the cardiac muscle and release ANP. Three milliliters of normal saline was injected during the day into the jugular vein of anesthetized rats that were pretreated with isoproterenol to stimulate pineal melatonin production. Animals were killed 15 min after the saline injection, and pineal NAT activity and pineal melatonin levels were measured. The saline injections caused no alteration in the elevated levels of either NAT or melatonin. These data suggest that the disparity in pineal NAT activity (which was high) and pineal melatonin (which was low), in animals swum at night, may not be caused by ANP which is released during strenuous exercise such as swimming.  相似文献   

14.
15.
Abstract: Herein we documented the response of pineal melatonin production to electrolytes known to be effective on pineal function in view of a possible circadian stage dependence. We studied the release of melatonin by perifused rat pineal glands at 2 different circadian stages corresponding to the middle of the light and dark periods, i.e., respectively, 7 and 19 HALO (Hours After Light Onset, L:D = 12:12). The initial efflux rates were, as expected, much higher in the perifusates of glands removed from rats sacrificed during the dark phase than of those removed during the light phase. After 3 hr of perifusion, melatonin release reached similar levels which were found constant up to the 8th hr of perifusion, whatever the circadian stage. Perifusion of the glands with physiological concentrations for the rat of calcium (5.2 mmol/1) and magnesium (1.34 mmol/1) resulted in a stimulatory effect on the pineal glands removed from rats sacrificed in the middle of the dark period (19 HALO), whereas no effects were observed on the pineal glands removed from rats sacrificed during the light (7 HALO). Lithium (0.28 and 0.55 mmol/1) was ineffective on melatonin release in pineal glands removed 7 and 19 HALO. Our results show differences in the initial efflux rates of melatonin and in the response of perifused pineal glands to calcium and magnesium according to the circadian stage.  相似文献   

16.
Abstract: Well-established circadian physiology supports the view that photoperiodic time measurement utilizes the coincidence between the presence of light and a photosensitive phase of a 'biological clock' to alter reproductive status—the so-called external coincidence model of seasonal breeding. In this review, we examine the mechanism whereby photoperiod interacts with presumed suprachiasmatic nuclei activity to allow endogenous melatonin to normally synchronize reproductive activity to the optimal time of year. The Romney Marsh sheep is particularly explored as an experimental model. It is suggested that the on/off activity of seasonal reproduction may be a robust mechanism able to be predictably manipulated by the judicious use of the light/dark cycle and exogenous melatonin, but firmly based on circadian principles.  相似文献   

17.
Microbiology of human immunodeficiency virus anorectal disease   总被引:3,自引:3,他引:0  
PURPOSE: Individuals who are seropositive for the human immunodeficiency virus are at high risk for opportunistic infection and anorectal disorders. Little prospective information is available regarding anorectal pathogens in these patients. METHODS: One hundred sixty-three HIV-seropositive patients presented to the colorectal clinic between 1989 and 1992. Forty-seven (29 percent) patients were thought to have an infectious process and were prospectively studied using a standardized multiculture protocol. RESULTS: Mean age was 33 (range, 19–59) years. All were male; high-risk behavior accounted for 87 percent of HIV transmissions. Presenting complaints included anorectal pain (79 percent), pus per anum (28 percent), and blood per anum (26 percent). Examination revealed perianal tenderness (60 percent), condyloma (38 percent), perianal ulcers (38 percent), and anal fissures (34 percent). Sixty-six sets of cultures were performed; 28 patients had one set, 15 had two sets, and 4 had three sets. Thirty-two of these 47 patients (68 percent) had positive cultures including herpes (50 percent), cytomegalovirus (25 percent),Neisseria gonorrhoeae (16 percent), chlamydia (16 percent), acidfast bacilli (2 percent), and others (9 percent). Six of 32 patients with positive cultures had more than one organism cultured. Sixteen (50 percent) patients with positive cultures were treated medically, 8 (25 percent) were treated surgically and 8 (25 percent) were treated with both modalities. Sixty-one procedures were performed on 17 patients for condylomata. Eighteen patients had 20 procedures for abscesses, 50 percent of whom had positive cultures for other than common bowel flora; all improved. Fourteen patients underwent 33 procedures for perianal fistulas.Mycobacterium fortuitum was cultured from one patient who required 13 procedures for abscesses and fistulas. Forty-five (96 percent) patients were followed for an average of 12.5 months ±2.9 SEM (range, 1–94 months). Symptoms were improved or resolved in 22 of 32 (69 percent) patients with positive cultures and in 11 of 13 (84 percent) with negative cultures. CONCLUSIONS: Specific pathogens may often be identified in human immunodeficiency virus-seropositive patients with anorectal disorders if aggressively sought. Although patients without specific pathogens identified may be expected to improve with planned empiric treatment, positive identification allows more directed therapy.  相似文献   

18.
Duodenal diverticula are a relatively common condition. They are asymptomatic, unless they become complicated, with perforation being the rarest but most severe complication. Surgical treatment is the most frequently performed approach. We report the case of a patient with a perforated duodenal diverticulum, which was diagnosed early and treated conservatively with antibiotics and percutaneous drainage of secondary retroperitoneal abscesses. We suggest this method could be an acceptable option for the management of similar cases, provided that the patient is in good general condition and without septic signs.  相似文献   

19.
Abstract: The abundance of gap junctions between rat pineal astrocytes formed by connexin43 (Cx43) was studied during development. Levels and distribution of Cx43 were measured by immunoblotting and indirect immunofluorescence, respectively. The amount of Cx43 in cells located within the gland was low until about the 7th postnatal day and increased to adult values between the 14th and 21st days postpartum. Although astrocytes, recognized by their vimentin immunoreactivity, were scarce before birth, they were abundant by the 7th postnatal day suggesting that the low levels of Cx43 found at this age corresponded to a low expression of this protein. Localization of the immunoreactivity to Cx43 and vimentin showed a close correlation, indicating that mature or immature pineal astrocytes form gap junctions made of Cx43. Since Cx43 levels attained their adult values at about the time the innervation and the functional state of the gland reached maturity (2–3 weeks after birth), it is proposed that astrocyte gap junctions are involved in the function of the adult rat pineal gland.  相似文献   

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